Interaction of the Melatonin/Ca2+-CaM Complex with Calmodulin Kinase II: Physiological Importance.

Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biologic activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation, where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to different proteins such as calmodulin: a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence supporting that melatonin binds to calmodulin in presence of calcium, and we discuss the effects of this indolamine on the activity of calmodulin kinase II as an inhibitor and as stimulator of calmodulin-dependent protein kinase II activity. We also provide a literature review supporting the relevance of melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient, conserved mechanism. Finally, we highlight the importance of antioxidant effects of melatonin on calmodulin preservation. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of calmodulin kinase II, the possible mechanisms involved, and the relevance on regulation of circadian rhythms and neurodevelopment. Finally, we describe evidence supporting that the binding of melatonin to calmodulin hydrophobic pockets may prevent the oxidation of methionine species with a shielding effect that preserves the functionality of calmodulin.

Recovery of Naringin-Rich Flavonoid Extracts from Agroresidues with Anxiolytic- and Antidepressant-like Effects in Mice.

Citrus paradisi species belong to the Rutaceae family, and it is commonly known as grapefruit. Grapefruit consumption involves a large amount of waste that goes to landfills and produces significant pollution affecting the human health. To examine this phenomenon, we designed an efficient chemical method that recovers naringin-rich flavonoid extracts from the fresh waste of grapefruits, by using the solvent impregnation resin method (SIR) with XAD-4 amberlite and either methanol or water as elution systems. Additionally, we focused on evaluating these extracts' anxiolytic- and antidepressant-like effects in behavioral predictive paradigms in mice. According to direct Principal Component Analysis (PCA) by NMR, and Direct Injection Electrospray Ionization-Mass Spectrometry (DIESI-MS), methanol extracts obtained after resin treatment were free of coumarin compounds and evinced had a high content of naringin. Poncirin, phenylalanine, chrysin 5,7-dimethyl ether, 5,7-dimethoxy-4'-hydroxyflavanone, 2,3-dihydro-2-(4-hydroxyphenyl)-5,6,7,8-tetramethoxy-4H-1-benzopyran-4-one, tetrahydrocurcumin, corchoionoside C, 6'-coumaroyl-1'-O-[2-(3,4-dihydroxyphenyl) ethyl]-ß-D-glucopyranoside were also detected. Naringin-rich methanol extract caused a clear anxiolytic-like effect in the Elevated Plus Maze (EPM) and the Hole-Board (HBT) Tests, increasing oral doses of this extract did not produce a sedative effect. A single oral dose caused an antidepressant-like effect in the Tail Suspension Test (TST), while repeated administrations of the methanol extract elicited a robust antidepressant effect in the Forced Swimming Test (FST) in mice. Our evidence highlights the importance of bioprospecting studies of organic waste with therapeutic potentials, such as anxiety and depression disorders.

Melatonin: A Neurotrophic Factor?

Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina's exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin's role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors.

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.

Antidepressant-like effects of a methanol extract of Leonotis nepetifolia in mice.

This study evaluated the antidepressant-like effects of a methanol extract of Leonotis nepetifolia in behavioural tests in mice. Our results showed that a single administration of the extract significantly reduced immobility behaviour in the tail suspension test, while three administrations were necessary to diminish immobility behaviour in the forced swimming test. A daily dose of the extract for 28 days improved body weight gain and significantly reduced corticosterone levels of mice exposed to chronic unpredictable mild stress. Metabolic profiling of the extract revealed that nepetaefolin, methoxynepataefolin, and 7-O-ß-glucoside luteolin were the main products. Acute and repeated administration of the extract produced antidepressant-like effects in animals subjected to chronic stress. Our results suggest the hypothalamus-hypophysis-adrenal axis participates in the antidepressant actions of the extract. These results show that alterations in behaviour elicited by stress can be prevented with L. nepetifolia treatment.

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity.

Melatonin (MEL) is a pleiotropic indolamine that reaches multiple intracellular targets. Among these, MEL binds to calmodulin (CaM) with high affinity. In presence of Ca2+, CaM binds to CaM-dependent kinase II (CaMKII). The Ca2+-CaM/CaMKII pathway regulates a myriad of brain functions in different cellular compartments. Evidence showing the regulation of this cellular pathway by MEL is scarce. Thus, our main objective was to study the interaction of MEL with CaM and its effects on CaMKII activity in two microenvironments (aqueous and lipidic) naturally occurring within the cell. In addition, colocalization of MEL with CaM in vivo was explored in mice brain hippocampus. In vitro CaM-MEL interaction and the structural conformations of CaM in the presence of this indoleamine were assessed through electrophoretic mobility and isoelectric point. The functional consequence of this interaction was evaluated by measuring CaMKII activity. Ca2+-CaM-MEL increased the activity of CaMKII in aqueous buffer but reduced the kinase activity in lipid buffer. Importantly, MEL colocalizes in vivo with Ca2+-CaM in the hippocampus. Our evidence suggests that MEL regulates the key cellular Ca2+-CaM/CaMKII pathway and might explain why physiological MEL concentrations reduce CaMKII activity in some experimental conditions, while in others it drives biological processes through activation of this kinase.

Low Doses of Ketamine and Melatonin in Combination Produce Additive Antidepressant-like Effects in Mice.

Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to six weeks to be effective with forty percent of patients being resistant to treatment, making it necessary to search for new antidepressant treatments. Ketamine, a phencyclidine hydrochloride derivative, given intravenously, induces a rapid antidepressant effect in humans. In mice, it causes increased neurogenesis and antidepressant-like effects. However, it also produces psychomimetic effects in humans and in rodents increases the locomotor activity. In contrast, melatonin, a hormone secreted by the pineal gland and synthesized in extrapineal sites, increases new neuron formation and causes antidepressant-like effects in adult rodents with no collateral effects. Here, we assessed the effects of a non-effective dose of ketamine in combination with melatonin (KET/MEL), both on neurogenesis as well as on the antidepressant-like effect in mice. Our results showed that KET/MEL combination increased neurogenesis and produced antidepressant-like effects without altering locomotor activity after both single and triple administration protocols. Our data strongly suggest that KET/MEL combination could be used to simultaneously promote neurogenesis, reverting neuronal atrophy and inducing antidepressant-like effects.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Cutin from Solanum Myriacanthum Dunal and Solanum Aculeatissimum Jacq. as a Potential Raw Material for Biopolymers.

Plant cuticles have attracted attention because they can be used to produce hydrophobic films as models for novel biopolymers. Usually, cuticles are obtained from agroresidual waste. To find new renewable natural sources to design green and commercially available bioplastics, fruits of S. aculeatissimum and S. myriacanthum were analyzed. These fruits are not used for human or animal consumption, mainly because the fruit is composed of seeds. Fruit peels were object of enzymatic and chemical methods to get thick cutins in good yields (approximately 77% from dry weight), and they were studied by solid-state resonance techniques (CPMAS 13C NMR), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), atomic force microscopy (AFM) and direct injection electrospray ionization mass spectrometry (DIESI-MS) analytical methods. The main component of S. aculeatissimum cutin is 10,16-dihydroxypalmitic acid (10,16-DHPA, 69.84%), while S. myriacanthum cutin besides of 10,16-DHPA (44.02%); another two C18 monomers: 9,10,18-trihydroxy-octadecanoic acid (24.03%) and 18-hydroxy-9S,10R-epoxy-octadecanoic acid (9.36%) are present. The hydrolyzed cutins were used to produce films demonstrating that both cutins could be a potential raw material for different biopolymers.

Antidepressant-like effect of Casimiroa pubescens root extracts.

In this study, we investigated the antidepressant-like effects of the hexane (HCP), ethyl acetate (ECP) and methanol (MCP) extracts of the roots of Casimiroa pubescens Ramírez (Rutaceae) using the forced swim test (FST). In an initial experiment, each extract was orally administered to mice only once 60 min before to the FST. In a second experiment, doses were administered 24, 7 and 1 h before testing. Our results showed that the triple administration of the extracts provided a stronger effect than single administration. However, the combination of HCP at 7.5 mg/kg and imipramine (IMI) at 12.5 mg/kg showed the greatest effect. The coumarins 3-(1',1', dimethyl allyl)-herniarin, auraptene, 8-geranyl-oxy psoralen, isopimpinellin and the flavonoid zapotin were isolated from the extracts. The hexane extract of C. pubescens showed an antidepressant-like activity, which may inspire further studies on developing new antidepressant agents.

Piper auritum Kunth (Piperaceae) improves the sexual performance of sluggish male rats through enhancing ejaculation.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper auritum Kunth is employed as an aphrodisiac in the traditional medicine, but corroborative evidence for such effect is scarce. AIM OF THE STUDY: The pro-sexual effect of an aqueous extract of P. auritum and its possible mechanisms were analyzed in two paradigms of male sexual function. MATERIAL AND METHODS: Effects of an aqueous extract of P. auritum (PA, single administration) were investigated in the fictive ejaculation, and copulatory behavior paradigms in sexually sluggish male rats. WAY 100635 (antagonist of 5-HT1A receptors), atosiban (antagonist of oxytocinergic receptors), L-NAME (inhibitor of the nitric oxide synthase) and baclofen (antagonist of GABAB receptors) were used as pre-treatments in order to investigate the role of different neurotransmitter systems in PA actions. Chemical profile of PA was determined by Gases Chromatography and Ultra Performance Chromatography-Electrospray Ionization-Masses Spectrometry (UPLC-ESI-MS). RESULTS: In males with retarded ejaculation, PA stimulated ejaculatory behavior and recovered electromyographic activity of pelvic musculature participating in seminal emission and ejaculation. All pre-treatments blocked stimulating effects of PA on the fictive ejaculation; additionally WAY 100635 interfered with PA actions on ejaculatory behavior. Safrol, apigenin dimethylether, myristicin, vaccihein A, sakuranin and sakuranetin flavonoids, were main constituents of PA, with possible participation in its pro-sexual effects. CONCLUSIONS: Pro-sexual effects of P. auritum elicited at level of ejaculation were mediated by several neurotransmitter systems, among which serotonin and its 5-HT1A receptors play an important role. Present findings support P. auritum reputation as an aphrodisiac, with potential use in delayed ejaculation disorder.

The Timing of Melatonin Administration Is Crucial for Its Antidepressant-Like Effect in Mice.

Melatonin is synthesized by the pineal gland with a circadian rhythm in synchrony with the environmental light/dark cycle. A gradual increase in circulating levels of melatonin occur after lights off, reaching its maximum around the middle of the dark phase. Agonists of melatonin receptors have proved effectiveness as antidepressants in clinical trials. However, there is contradictory evidence about the potential antidepressant effect of melatonin itself. Herein we studied melatonin administration in mice at two zeitgeber times (ZT; ZT = 0 lights on; 12:12 L/D), one hour before the beginning (ZT11) and at the middle (ZT18) of the dark phase after either a single or a three-dose protocol. Behavioral despair was assessed through a forced-swimming test (FST) or a tail suspension test (TST), at ZT18.5. A single dose of 4 mg/kg melatonin at ZT11 was effective to reduce the immobility time in both tests. However, acute administration of melatonin at ZT18 was not effective in mice subjected to FST, and a higher dose (16 mg/kg) was required to reduce immobility time in the TST. A three-dose administration protocol of 16 mg/kg melatonin (ZT18, ZT11, and ZT18) significantly reduced immobility time in FST. Data indicate that the timely administration of melatonin could improve its antidepressant-like effect.

Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression.

Mood disorders are a spectrum of neuropsychiatric disorders characterized by changes in the emotional state. In particular, major depressive disorder is expected to have a worldwide prevalence of 20% in 2020, representing a huge socio-economic burden. Currently used antidepressant drugs have poor efficacy with only 30% of the patients in remission after the first line of treatment. Importantly, mood disorder patients present uncoupling of circadian rhythms. In this regard, melatonin (5-methoxy-N-acetyltryptamine), an indolamine synthesized by the pineal gland during the night, contributes to synchronization of body rhythms with the environmental light/dark cycle. In this review, we describe evidence supporting antidepressant-like actions of melatonin related to the circadian modulation of neuroplastic changes in the hippocampus. We also present evidence for the role of melatonin receptors and their signalling pathways underlying modulatory effects in neuroplasticity. Finally, we briefly discuss the detrimental consequences of circadian disruption on neuroplasticity and mood disorders, due to the modern human lifestyle. Together, data suggest that melatonin's stimulation of neurogenesis and neuronal differentiation is beneficial to patients with mood disorders. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Anxiolytic- and antidepressant-like effects of an aqueous extract of Tanacetum parthenium L. Schultz-Bip (Asteraceae) in mice.

AIM: Tanacetum parthenium L. Schultz-Bip (Asteraceae) is widely used worldwide in traditional medicine for the treatment of convulsions and culture-bound syndromes such as susto (fear). The aim of this work was to evaluate the anxiolytic- and antidepressant-like effects of an aqueous extract of T. parthenium in behavioral paradigms in mice. The effects of T. parthenium were compared with those produced by anxiolytic and antidepressant drugs. We carried out the chemical characterization of the main constituents of T. parthenium. The involvement with the GABAergic and serotoninergic neurotransmitter systems were explored be means of synergic and antagonist experiments. MATERIALS AND METHODS: The anxiolytic-like effect was evaluated using the Burying Behavior Test (BBT) and the Elevated Plus-Maze Test (PMT). The antidepressant-like effect was evaluated in the Forced Swimming Test (FST), and ambulatory activity was assessed in the Open Field Test (OFT). Employing the behavioral tests, synergism and antagonism experiments with Alprazolam, Muscimol, and Picrotoxin were carried out in the PMT. In a series of independent experiments, concomitant administration of T. parthenium and Alprazolam, Fluoxetine, or p-chlorophenylalanine were conducted in the FST. For chemical characterization, High-Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry (HPLC-ESI-MS) analysis was performed. RESULTS: T. parthenium exerts clear anxiolytic- and antidepressant-like effects in mice, without affecting the ambulatory activity of the experimental subjects. CONCLUSIONS: Anxiolytic- and antidepressant-like T. parthenium effects result, at least part from the involvement of the GABAergic system. Our results support the use of Tanacetum parthenium in traditional medicine and suggest its therapeutic potential in the comorbid anxiety and depression.

Involvement of the GABAergic system in the neuroprotective and sedative effects of acacetin 7-O-glucoside in rodents.

PURPOSE: Characterization of sedative, possible anticonvulsant, and protective effects of Acacetin-7-O-glucoside (7-ACAG). METHODS: 7-ACAG was separated and its purity was analyzed. Its sedative and anti-seizure effects (1, 10, 20, and 40 mg/kg) were evaluated in male mice. Synaptic responses were acquired from area CA1 of hippocampal slices obtained from male Wistar rats. Rats were subjected to stereotaxic surgeries to allow Electroencephalographic (EEG) recordings. Functional recovery was evaluated by measuring the time rats spent in completing the motor task. Then the rats were subjected to right hemiplegia and administered 7-ACAG (40 mg/kg) 1 h or 24 h after surgery. Brains of each group of rats were prepared for histological analysis. RESULTS: Effective sedative doses of 7-ACAG comprised those between 20 and 40 mg/kg. Latency and duration of the epileptiform crisis were delayed by this flavonoid. 7-ACAG decreased the synaptic response in vitro, similar to Gamma-aminobutyric acid (GABA) effects. The flavonoid facilitated functional recovery. This data was associated with preserved cytoarchitecture in brain cortex and hippocampus. CONCLUSIONS: 7-ACAG possesses anticonvulsive and sedative effects. Results suggest that GABAergic activity and neuroprotection are involved in the mechanism of action of 7-ACAG and support this compound's being a potential drug for treatment of anxiety or post-operative conditions caused by neurosurgeries.

Antidepressant-like and toxicological effects of a standardized aqueous extract of Chrysactinia mexicana A. Gray (Asteraceae) in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: C. mexicana A. Gray (Asteraceae) is a native of North America plant. In Mexico׳s folk medicine it is used for the fever, rheumatism and as a diuretic, antispasmodic, general tonic or adaptogenic herb, and as a stimulant agent. The aim of the study was to examine the antidepressant-like properties of an aqueous extract of C. mexicana (Cm), in order to scientifically describe its potential value in the management of depressive disorders. To evaluate the acute and subacute toxic effects of Cm and effects on hepatic and biochemical functions in mice. MATERIALS AND METHODS: Antidepressant-like effects of Cm were evaluated in the Forced swimming and suspension tail tests (FST and TST), the ambulatory activity was measure in the Open Field Test (OFT), motor coordination was evaluated in the inverted screen and gyratory roller (IST and Rota-rod), the biochemical and histopathological analysis were carried out. Phytochemical studies of organic and aqueous extracts of Cm were thoroughly conducted. RESULTS: Cm produced a significant reduction of the immobility time both FST and in TST, without affect the ambulatory activity of experimental mice. Cm did not produce any damage in the hepatic functions, nor produce any significant change in the morphological tissue of organs examined. CONCLUSIONS: Chrysactinia mexicana induces a clear antidepressant-like effect in mice, without affect any basic functions. The consumption of this medicinal plant does not represent risk for health. The chemical analysis showed the flavonoids free and glycosides mainly.

Anti-depressant-like effect of kaempferitrin isolated from Justicia spicigera Schltdl (Acanthaceae) in two behavior models in mice: evidence for the involvement of the serotonergic system.

We evaluated the antidepressant-like effect of kaempferitrin (Km) isolated from the plant Justicia spicigera (Asteraceae), which is used in traditional medicine for relieving emotional disorders, such as "la tristeza" (sadness or dysthymia) and "el humor" (mood changes). The actions of Km were evaluated in a forced swimming test (FST) and a suspension tail test (TST) in mice. We explored the involvement of the serotonergic system and the hypothalamic-hypophysis-adrenal axis (HPA) in the antidepressant-like effect of Km. To evaluate nonspecific effects of Km on general activity, the open field test (OFT) was performed. Km at 5, 10, and 20 mg/kg induced an antidepressant-like effect. Sub-effective dose of Km (1 mg/kg) produced a synergistic effect with imipramine (6.25 mg/kg) and fluoxetine (10 mg/kg) but not with desipramine (3.12 mg/kg). Pretreatment with p-chlorophenylalanine methyl ester (PCPA), a serotonin synthesis inhibitor, N-{2-(4-(2-methoxyphenyl)-1-piperazinyl}-N-(2-pyridinyl)cyclohexecarboxamide (WAY-100635), a selective 5-HT1A receptor antagonist, and 8OH-DPAT, a selective 5-HT1A agonist, but not pindolol (10 mg/kg) blocked the anti- immobility effect induced by Km. Taken together, these results indicate that the antidepressant-like effect of Km is related to the serotonergic system, principally 5-HT1A. This effect was not related to changes in locomotor activity.

Central nervous system effects and chemical composition of two subspecies of Agastache mexicana; an ethnomedicine of Mexico.

ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana subspecies mexicana (Amm) and xolocotziana (Amx) are used in Mexican traditional medicine to relief cultural affiliation syndromes known as "susto" or "espanto", for "nervous" condition, and as a sleep aid. Despite its intensive use, neuropharmacological studies are scarce, and the chemical composition of the aqueous extracts has not been described. Aims of the study are: (1) To analyze the chemical composition of aqueous extracts from aerial parts of Amm and Amx. (2) To evaluate the anxiolytic-like, sedative, antidepressant-like effects. (3) Analyze the general toxic effects of different doses. MATERIALS AND METHODS: Anxiolytic-like and sedative effects were measured in the avoidance exploratory behavior, burying behavior and the hole-board tests. The antidepressant-like actions were studied in the forced swimming and tail suspension tests. Finally, general activity and motor coordination disturbances were evaluated in the open field, inverted screen and rota-rod tests. The acute toxicity of Amm and Amx was determined by calculating their LD50 (mean lethal dose). The chemical analyses were performed employing chromatographic, photometric and HPLC-ESI-MS techniques. RESULTS: Low doses of Amm and Amx (0.1σ1.0mg/kg) induced anxiolytic-like actions; while higher doses (over 10mg/kg) induced sedation and reduced the locomotor activity, exerting a general inhibition in the central nervous system (CNS). CONCLUSIONS: Results support the use of Amm and Amx in traditional medicine as tranquilizers and sleep inducers. Additionally, this paper contributes to the knowledge of the chemical composition of the aqueous extracts of these plants.

Anxiolytic-like and antinociceptive effects of 2(S)-neoponcirin in mice.

STUDY AIMS: 2(S)-neopincirin (NEO) is a constituent from of Clinopodium mexicanum, which is used in traditional Mexican herbal medicine for its tranquilizing and analgesic properties. This study investigated the anxiolytic-like, sedative and antinociceptive effects of NEO in several mice models. MATERIAL AND METHODS: The anxiolytic-like effect was evaluated in the hole-board (HBT) and Open Field Tests (OFT); sedative effect was evaluated in sleeping time induced by sodium pentobarbital, and its antinociceptive actions were measured in the hot plate test. To evaluate if the GABA receptor could be involved in the anxiolytic-like effect produced by NEO, in independent experiments, the effects produced by co-administration of NEO plus muscimol (MUS) and NEO plus Pitrotoxin (PTX) were evaluated in the HBT. RESULTS: NEO was isolated from Clinopodium mexicanum leaves. The NMR, MS and optic rotation data helped establish its identity as (2S)-5-hydroxy-4'-methoxyflavanone-7-O-{ß-glucopyranosyl-(1→6)-ß-rhamnoside}. NEO showed an anxiolytic-like effect and was able to counter the nociception induced by a thermal stimulus in a dose-dependent manner. PTX blocked the anxiolytic-like effect of NEO, while MUS was able to enhance it. CONCLUSIONS: The findings of present work demonstrated that NEO possesses anxiolytic-like and antinociceptive effects in mice. Such effects are not associated with changes in the locomotor activity. These results supported the notion that anxiolytic-like effect of NEO involves the participation of GABAergic system.

Los flavonoides y el Sistema Nervioso Central / Flavonoids and Central Nervous System

The aim of the present study was to show the most relevant aspects of the flavonoids such as their origin, sources, chemical structures, and metabolism in the body human. We offer a brief review about their antiallergic, anti-cancer, anti-inflammatory, and analgesic properties. This review shows their effects on CNS and evidences their pharmacologic potential in the therapeutics of the mental disorders. Flavonoids may have existed in nature for over 1 billion years and thus have interacted with evolving organisms. These compounds are molecules of low molecular mass, abundant in all berries and citric fruits, chocolate, nuts, red wine, and several medicinal plants. Flavonoids interact with several enzymes responsible for the transport of xenobiotics to the brain, which are considering modifiers of the biological response. Perhaps the most studied have been their anti-oxidant properties, which have met reflected in his capacity to protect to the cells of the oxidative stress, implicated several pathologies associated with aging, such as Alzheimer's and Parkinson's diseases. In the last 30 years, a intensive research about the effects of the flavonoids on CNS has been carried out; in this regard, flavonoids have showed effective effects as anxiolytic, antidepressants, and anticonvulsive drugs, and although their actions in the CNS occur through a variety of interactions with different receptors and signaling pathways, it has been demonstrated that these effects are mediated principally by GABA, in particular GABA A receptors, which these has led them to being postulates as a new benzodiazepines family, but without the side effects of these.

El propósito de esta revisión fue describir los aspectos más relevantes de los flavonoides como su origen, sus fuentes y metabolismo, sus propiedades farmacológicas como antialérgicos, anticancerosos, anti-inflamatorios, analgésicos. También revisamos sus efectos sobre el SNC poniendo en evidencia su potencial farmacológico en la terapéutica de los trastornos mentales. Los flavonoides son sustancias de bajo peso molecular que han estado presentes en la naturaleza durante millones de años. El hombre los consume en la dieta ya que están presentes de forma abundante en los vegetales, las frutas rojas como las fresas, zarzamoras, frutas cítricas, el chocolate, las nueces, el vino tinto y en varias plantas medicinales. Estos compuestos poseen una amplia gama de actividades farmacológicas entre las que destacan sus propiedades anti-oxidantes, las cuales les confieren capacidad de proteger a las células del estrés oxidativo relacionado con patologías asociadas al envejecimiento, como las enfermedades de Alzheimer y Parkinson. En los últimos 30 años se ha realizado una intensa investigación sobre sus acciones en el SNC, entre las que sobresalen sus propiedades como ansiolíticos, sedantes, antidepresivos y anticonvulsivos. Se ha demostrado que estos efectos son mediados principalmente por los receptores GABA, en particular los receptores GABA A, por lo que los flavonoides han sido reconocidos como una nueva familia de benzodiazepinas, con la ventaja de no presentar los efectos colaterales que éstas producen.